A study of new therapeutic candidates for Alzheimer's disease utilizing microglia activation by

在阿尔茨海默病的早期阶段，神经炎症被认为是重要的，神经胶质细胞释放的细胞因子在这一现象的进展中发挥了作用。由于脂多糖(LPS)可以在实验中诱导类似的脑部炎症变化，我们研究了胰高血糖素样肽-1(GLP-1)对内毒素诱导的E18大鼠大脑皮质星形胶质细胞细胞因子表达的影响。逆转录聚合酶链式反应显示，GLP-1可抑制脂多糖诱导的IL-β、IL-6和iNOS的表达。此外，通过cAMP系统和cREB的磷酸化，酶联免疫吸附试验显示细胞培养上清液中IL-1β的多肽水平随着GLP-1的作用而降低。此外，我们还研究了GLP-1对胶质细胞谷氨酸转运体GLT-1基因表达的影响，因为在阿尔茨海默病中谷氨酸转运体减少，并被3-淀粉样蛋白抑制了对胶质细胞的谷氨酸摄取，这一现象可能导致谷氨酸的兴奋毒性增加。GLP-1可上调培养的星形胶质细胞GLT-1mRNA的表达。我们认为，在中枢神经系统的病理状态下，GLP-1可能通过增加胶质谷氨酸转运体来保护神经元免受兴奋性毒性。这些结果提示，GLP-1可能通过抑制兴奋性毒性和抑制小胶质细胞激活后促炎细胞因子的产生而发挥神经保护作用。

In the early stage of Alzheimer's disease, neuroinflammation is considered to be important, and cytokines released from glia play a role in progression of the phenomena. Since lipopolysaccharide (LPS) could experimentally induce similar inflammatory changes in the brain, we examined the effects of glucagon-like peptide-1 (GLP-1) on LPS-induced cytokine expression in cultured astrocytes derived from the E18 rat's cortex. RT-PCR analysis showed that GLP-1 suppressed LPS-induced IL-β,IL-6 and iNOS expressions. Furthermore, ELISA demonstrated that peptide levels of IL-1β in the culture medium decreased in response to GLP-1 through the cAMP system and CREB phosphorylation. Furthermore, we investigated the effects of GLP-1 on the glial glutamate transporter, GLT-1, mRNA expression, since a decrease in glutamate transporters in Alzheimer's disease, and an inhibition of glutamate uptake into glia by (3-amyloid protein were reported, which phenomena may result in an increase in excitotoxicity by glutamate. GLP-1 treatment increased the GLT-1 mRNA expression in cultured astrocytes. We suggest that GLP-1 may protect neurons from excitotoxicity through an increase in glial glutamate transporters in the pathological conditions of the central nervous system. These results suggest that GLP-1 has neuroprotective effects through the inhibition of excitotoxicity as well as suppression of pro-inflammatory cytokines production after microglia activation.